The human tumor predisposition disease von Recklinghausen's neurofibromatosis type I (NF1) is one of the most common genetic disorders of the nervous system, affecting 1 in 3000 individuals worldwide. It is caused by mutation in the NF1 tumor suppressor gene, which encodes a GTPase Activating Protein (GAP) that negatively regulates p21-RAS signaling. Dermal and plexiform neurofibromas, as well as malignant peripheral nerve sheath tumors and other malignant tumors are serious complications of NF1. Neurofibromas are complex tumors and composed mainly of abnormal local cells including: Schwann cells, nerves, endothelial cells, fibroblasts and additionally a large number of infiltrating inflammatory mast cells. However, little is known about the molecular mechanisms mediating the initiation and progression of these complex tumors, or the identity of the specific cell type that gives rise to cutaneous neurofibromas. Recent work in our laboratory has identified a novel population of neural stem cells residing in the dermis termed skin-derived precursors (SKPs) as the cell of origin of dermal neurofibroma and generated the first mouse model for this complex cutaneous tumor. These studies also provide evidences that additional signals from non-neoplastic cells in the tumor microenvironment play essential roles in neurofibroma formation. The emerging evidence points to mast cell, neurons and steroid hormone, as crucial early contributors to tumorigenesis. Based upon our preliminary data, we hypothesize that inhibitors to these specific tumor constituents will be able to prevent or delay neurofibroma development. The objectives of this proposal are to systematically examine the role of non-neoplastic cells in the tumor microenvironment in the initiation and progression of dermal neurofibromas. These studies aim to identify potential therapeutic windows that can target these tumors at the earliest stages. Specifically, we will (1) define early, initiating geneic and tumor microenvironmental events that dictate dermal neurofibroma development and (2) determine phenotypic consequences of inhibition of these specific constituents in the tumor microenvironment during early phases of neurofibroma development. This research plans are novel because we have uncovered unique paracrine interactions between the neoplastic cells (the Schwann cells) and their microenvironment that are required for tumor formation. Moreover, this proposal not only will provide important insights into the molecular and cellular pathogenesis of neurofibroma, but also could lead directly to new and potentially effective therapies aimed at delaying or preventing tumor formation in NF1 patients, where none exist today. In addition, while focused on neurofibroma, this work raises the exciting possibility that the surrounding non-neoplastic cells in the tumor environment may also impact the growth of other tumor types. An increased understanding of the role of non-neoplastic tumor-associated cells may lead to new directions for cancer therapy and prevention. PUBLIC HEALTH RELEVANCE: The objectives of this proposal are to systematically examine how the neighboring non- cancerous cells in the tumor microenvironment dictate the initiation and progression of tumor development. An increased understanding of the role of non-neoplastic tumor-associated cells may lead to new directions for cancer therapy and prevention.